natural IgM produced by B-1 cells and infection-induced IgM, produced by B-1 and B-2 cells, are required for immune protection against many viruses, including influenza. Secreted IgM acts as a mucosal immune barrier, but it also affects the adaptive immune response. In its absence IgG responses are reduced, but the mechanisms of this effect are unknown. Recent data also suggest a central role for lgM+ memory B cells in long-term maintenance of humoral immunity. The developmental pathways of lgM+ memory induction and the mechanisms through which IgM regulates the adaptive immune response have not been fully delineated. This project aims to fill this gap in knowledge, because the establishment of protective humoral immunity is the basis for nearly all current vaccines, and the lack of long-term immunity one of the biggest hurdles in effective vaccine design. The proposal will test the hypothesis that IgM is a non-redundant component of humoral immunity that regulates the induction and maintenance of virus-specific B cell responses and is generated by multiple B cell subsets in mice, whose homologues are present in non-human primates and in humans. Specific Aim 1 will test whether secreted (s) IgM inhibits germinal center formation by providing a direct negative-feedback loop for antigen-specific B cells via FcR-binding. We will determine the individual and combined effects of signaling via the two sIgM-FcR on influenza-specific extrafollicular and germinal center B cell responses, IgG and IgM memory induction and plasma cell development. Aim 2 will study the induction of lgM+ memory responses to influenza virus infection and vaccination in mice by following influenza-specific B cells to establish their lineage origins (B-1 and B-2), their antigen-spectrum and protective capacity against homo and heterosubtypic infection during an influenza challenge. Aim 3 will evaluate antigen-specific IgG titers and IgM-memory B cells to Measles virus H-protein in NHP and to determine the homologues of lgM+ B-1 and B- 2 cells in NHP so as to relate this information to parallel studies conducted in humans by Core C, with the ultimate goal to vigorously test each animal model for their predictive value for antiviral immunity in humans.